Reduced-dose WBRT combined with SRS for 1-4 brain metastases aiming at minimizing neurocognitive function deterioration without compromising brain tumor control.

Background and purpose: To minimize cognitive decline without increasing brain tumor recurrence (BTR) by reduced-dose whole-brain radiotherapy (RD-WBRT) (25 Gy, 10 fractions) + stereotactic radiosurgery (SRS) in patients with ≤ 4 brain metastases. Materials and methods: Eligible patients with ≤ 4 brain metastases on contrast-enhanced MRI and Karnofsky Performance Status ≥ 70. The primary endpoint was the non-inferiority of BTR at distant sites in the brain (BTR-distant)-free survival at 6 months compared to that of the standard dose (SD)-WBRT (30 Gy, 10 fractions) + SRS arm in a randomized clinical trial (JROSG99-1) of SRS with/without SD-WBRT. Secondary endpoints included BTR at any brain sites (BTR-all) and neurocognitive function assessed by a six-test standardized battery. Results: Forty patients from seven institutions were enrolled (median age 69 years). The primary tumor site was a lung in 28 patients; 20 patients had a solitary brain metastasis. The median survival time was 19.0 months (95 %CI: 13.8 %-27.5 %). The BTR-distant-free survival at 6 months was 76.9 % (59.5 %-87.7 %), which is comparable to that of historical control although predetermined non-inferiority (>71 %) could not be confirmed (p = 0.16). The cumulative incidence of BTR-all at 6 months accounting for the competing risk of death was 23.0 % (11.4-37.1), which was not worse than that of historical control (p = 0.774). The frequency of the cumulative incidence of persistent cognitive decline at 6 months was 48.6 % under the [>2.0 SD in ≥ 1 test] definition. Conclusions: RD-WBRT may yield comparable intracranial tumor control when combined with SRS, and may reduce the risk of neurocognitive decline compared to that after SD-WBRT.

Clinical value of serum biomarkers, squamous cell carcinoma antigen and apolipoprotein C-II in follow-up of patients with locally advanced cervical squamous cell carcinoma treated with radiation: A multicenter prospective cohort study.

There are currently no reliable, established serum biomarkers to predict the prognosis of radiotherapy for advanced cervical cancer. We aimed to identify serum biomarkers for survival after radiotherapy for cervical cancer. In this multicenter prospective cohort study, the usefulness of pre- and posttreatment serum protein levels of potential biomarkers, including squamous cell carcinoma antigen (SCC-Ag), apolipoprotein C-II (ApoC-II), matrix metalloproteinase (MMP)1, and MMP2, were evaluated together with clinical factors in 145 cervical cancer patients in order to determine their suitability to predict survival. Progression-free survival (PFS) was the primary endpoint, and overall survival (OS), pelvic PFS (PPFS), and distant metastasis-free survival (DMFS) were the secondary endpoints. Blood samples were collected before and 1 month after radiotherapy to measure serum biomarker levels. ApoC-II was measured using a monoclonal antibody-based enzyme-linked immunosorbent assay, which was developed for this purpose. Kaplan-Meier method, log-rank test, and univariate and multivariate Cox proportional hazards models were used for statistical analyses. In multivariate analysis, larger tumor size was independently associated with shorter PFS, OS, PPFS, and DMFS, while longer overall treatment time was independently associated with shorter PPFS. Higher pretreatment SCC-Ag (P < 0.001) was associated with shorter DMFS. Higher posttreatment SCC-Ag (P = 0.017) was also associated with shorter DMFS. Pretreatment ApoC-II was associated with PPFS in univariate analysis (P = 0.048), but not in multivariate analysis. Patients with pretreatment ApoC-II levels ≤ 25.8 µg/ml had shorter PPFS than those with pretreatment ApoC-II levels > 25.8 µg/ml (P = 0.023, log-rank test). Pre- and posttreatment serum SCC-Ag and pretreatment serum ApoC-II levels may be important biomarkers to predict survival outcomes of patients with cervical cancer after radiotherapy. Pre- and posttreatment SCC-Ag and pretreatment ApoC-II might be useful in clinical settings for screening patients to improve treatment strategies in cervical cancer.

Monitoring expiratory carbon monoxide to study the effect of complete smoking cessation on definitive radiation therapy for early stage glottic carcinoma.

BACKGROUND: Previous studies reported that cigarette smoking during radiation therapy was associated with unfavorable outcomes in various cancers using medical interviewing or monitoring of cotinine. Here, we evaluated the effect of smoking cessation on definitive radiation therapy for early stage glottic carcinoma by monitoring expiratory carbon monoxide (CO). MATERIAL AND METHODS: We enrolled 103 patients with early glottic carcinoma (T1N0/T2N0 = 79/24) who underwent conventional radiotherapy between 2005 and 2016. The median age was 70 years. Pathologically, all patients had squamous cell carcinoma. Since 2009, we confirmed smoking cessation before radiation therapy by medical interviews. Since 2014, we measured expiratory CO to strictly monitor smoking cessation. The patients were divided according to diagnosis years: 'no cessation' (2005-2008), 'incomplete cessation' (2009-2013), and 'complete cessation' (2014-2016). We retrospectively analyzed the local recurrence rate and disease-free survival (DFS). RESULTS: The median follow-up period was 60.1 months (range, 1.9-110.0 months). The 2-year local recurrence rate in the 'complete cessation' group was 5.3% and tended to be lower than that in the 'incomplete cessation' group (13.7%) and 'no cessation' group (21.2%). Multivariate analysis revealed that 'no cessation' was a risk factor for DFS (hazard ratio [HR] = 4.25) and local recurrence rate (HR = 16.5, p < .05) compared to 'complete cessation.' DISCUSSION: We confirmed that the 'complete cessation' group had better prognosis than the 'no cessation' group by monitoring expiratory CO during radiation therapy for early stage glottic carcinoma. Moreover, monitoring expiratory CO was easier and more suitable than conventional methods for evaluating smoking cessation because it provided real-time measurements.

Radiation Therapy Alone for Human Papillomavirus-Related Squamous Cell Carcinoma of the Oropharynx: A Single-Arm, Phase 2 Study.

PURPOSE: Human papillomavirus (HPV)-related squamous cell carcinoma of the oropharynx (OPSCC) is extremely radiosensitive. Radiation therapy plus high-dose cisplatin remains the standard of care but causes long-term toxicity. Treatment deintensification approaches that reduce toxicity while maintaining survival are desirable for HPV-related OPSCC. METHODS AND MATERIALS: We conducted a single-arm, multicenter, phase 2 trial. Patients with newly diagnosed, biopsy-proven, American Joint Committee on Cancer (seventh edition) stage III or IV OPSCC positive for both p16 and HPV DNA were eligible. Patients with T4, N3, or T1N1 disease were excluded. Smoking history was not included in eligibility criteria. Patients received intensity modulated radiation therapy (IMRT) of 70 Gy in 35 fractions or 70.4 Gy in 32 fractions without chemotherapy. The primary endpoint was complete response or complete metabolic response 10 weeks after IMRT completion. RESULTS: Between September 13, 2013, and November 15, 2016, 39 patients were enrolled according to a 2-stage Simon design. Twenty-three patients (59%) had smoked for more than10 pack-years. Thirty-six patients (92%) had tumors genotyped as HPV16. Thirty-seven patients (95%) received full-dose radiation therapy and 35 (90%) had complete response or complete metabolic response. Median follow-up was 51 months (interquartile range, 41-63 months). One patient (3%) had regional recurrence and 3 (8%) had distant metastasis. One patient died of disease. The 2-year progression-free survival rate was 94% (95% CI, 81%-99%), and the 2-year overall survival rate was 100%. Common grade 3 adverse events during IMRT included mucositis in 10 patients (26%) and dysphagia in 7 patients (18%). No patients were dependent on a feeding tube at 1 month after IMRT completion. No grade 3 or 4 late adverse events were observed. CONCLUSIONS: IMRT alone is associated with excellent response as well as reduced toxicity and could be a treatment option for carefully selected patients with locally advanced "true" HPV-related OPSCC. Further studies are warranted.

High-dose rate intracavitary brachytherapy pretreatment dwell position verification using a transparent applicator.

PURPOSE: The major errors in HDR brachytherapy are related to treatment distance, almost all of which are caused by incorrect applicator information. The aim of this study is to propose a quick pretreatment verification method to evaluate channel length and dwell position with a transparent applicator, which, in addition, is suitable as an education tool to assist in the understanding of the applicator structure. METHODS: A transparent applicator model was fabricated using a three-dimensional printer and transparent resin. Its aim is to be a replica of a real gynecological applicator. The pretreatment verification is performed by observing the planned dwell positions of a check cable inside a transparent applicator. A digital camera acquired images and the dwell positions of the radioactive source and check cable were evaluated by comparing them with respect to the theoretical dwell positions marked by the proper x-ray marker. The potential effectiveness of verification using a transparent applicator was also evaluated using brachytherapy events reported in the literature. RESULTS: The transparent applicator closely resembles the real applicator in shape and had an error of less than 0.2 mm. The average dwell position displacement between the radioactive source and check cable was 0.4 mm. The analysis of brachytherapy events showed that channel-length, dwell-position, and step-size errors made up 50% of all events, but affected 64% of all patients. CONCLUSIONS: The transparent applicator model enables a noninvasive, repeatable verification of the channel length and dwell positions to be performed before treatment. This verification has the potential to help prevent common errors in treatment delivery. In addition, the transparent applicator model can be used as a teaching tool to help clinicians understand the operation of the applicator, lowering the risk of events.

Impact of different Ir-192 source models on dose calculations in high-dose-rate brachytherapy.

In high-dose-rate brachytherapy, the geometry of the radioactive source is sometimes updated. Some institutions use a different source model for the dose calculation in treatment planning and treatment. The effects of this discrepancy were examined for four types of treatment plans, and ten patients were selected for each treatment plan. The impact of different source models depended on the types of treatment plan, patients, and dose index. To reduce the uncertainty and improve the reliability of the data, it would be better to use more robust metrics (D90 and D2cc) for treatment planning evaluation in facilities with this problem.

[A Case of Unresectable Advanced Gastric Cancer Treated with Radiotherapy and Trans-Arterial Embolization, Resulting in Effective Hemostasis].

We report the case of a 70-year-old man with unresectable advanced gastric cancer because of invasion to the pancreas and multiple liver metastases. He could have continued with fourth-line chemotherapy by controlling intermittent bleeding from the cancer by means of 2 rounds of radiotherapy and trans-arterial embolization. The serum hemoglobin level declined to 4.5 g/dL during second-line chemotherapy. As the venous bleeding from the cancer was difficult to control by endoscopic hemostasis, radiotherapy with 40 Gy/20 fractions was applied to the cancer. We were able to restart chemotherapy after the hemostasis, but 6 months later, the serum hemoglobin level declined to 6.1 g/dL. Additional radiotherapy of 20 Gy/10 fractions was delivered to the tumor, and successful hemostasis was achieved; the serum hemoglobin level reached 7.5 g/dL. However, a contrast-enhanced CT, which was performed 3 weeks later, demonstrated extravasation from the cancer into the gastric cavity. We conducted trans-arterial embolization, and the patient no longer required transfusion. We planned to restart chemotherapy soon, but after 1 month, he died of pneumonia.

[A Case of Esophageal Cancer Metastases to the Skin].

Skin metastases from esophageal cancer are comparatively rare but have poor prognosis. Here, we report a case of esophageal cancer metastases to the skin. A 70-year-old man was admitted to our hospital for nodules with ulceration in the nose, and biopsy revealed a metastatic carcinoma. FDG-PET indicated FDG accumulation in the skin, liver, and esophagus, while an endoscopic study of the upper gastrointestinal tract showed a type 3 tumor at the upper mid-thoracic esophagus. We diagnosed the patient with metastatic esophageal cancer and administered chemotherapy. Radiation therapy (40 Gy/20 Fr) was simultaneously administered for the tumor in the nose because the patient's quality of life (QOL) decreased daily owing to pain and bleeding caused by metastatic skin cancer. The radiation therapy reduced the size of the tumor in the nose, but the tumor had remained along with the presence of a scar 3 to 6 months after the start of radiation therapy. Radiation effectively promoted the QOL of our patient with skin metastases.

External-beam radiotherapy for clinically localized prostate cancer in Osaka, Japan, 1995-2006: time trends, outcome, and risk stratification.

PURPOSE: To establish an initial database of external-beam radiotherapy (EBRT) for clinically localized prostate cancer used in Osaka, Japan, and, by analyzing the results of the Osaka multicenter cooperative study, to determine time trends, outcome, and applicability of existing and the authors' original risk stratification methods. PATIENTS AND METHODS: Data of 652 patients with clinically localized prostate cancer (T1-4 N0 M0) were accrued from July to December 2007. These patients had been treated from 1995 through 2006 with consecutive definitive EBRT of > or = 60 Gy at eleven institutions, mainly in Osaka. Altogether, 436 patients were eligible for analysis using several risk stratification methods, namely, those of D'Amico et al., the National Comprehensive Cancer Network (NCCN), and Seattle, as well as the authors' original Prostate Cancer Risk Index (PRIX). RESULTS: The number of patients showed a tenfold increase over 10 years, together with a rapid spread of the use of Gleason Score from 0% to > 90% of cases. The dominant RT dose fractionation was 70 Gy/35 fractions (87%). Hormone therapy had been administered to 95% of the patients and the higher PRIX corresponded to the higher rate of hormone usage. 3- and 5-year biochemical relapse-free survival (bRFS) rates were 85% and 70%, respectively. The D'Amico (p = 0.132), NCCN (p = 0.138), Seattle (p = 0.041) and PRIX (p = 0.044) classifications showed weak or no correlation with bRFS, while the own modified three-class PRIX (PRIX 0, 1-5, 6) showed a strong correlation (p = 0.002). CONCLUSION: The use of prostate EBRT in Japan is still in its infancy, but is rapidly expanding. The short-term outcomes have been satisfactory considering the moderate RT dose. A very high rate of hormone usage may affect the outcome favorably, but also may compromise the usefulness of current risk stratification.

[Multidisciplinary strategy for lung cancer patients with bone metastasis].

The fall of QOL by bone metastasis poses a problem with the increase in lung cancer. The examples of long-term survival of lung cancer are also increasing by progress of chemotherapy or molecular-targeted therapy. Now, in addition to the conventional radiotherapy, the multidisciplinary treatment including a newer bisphosphonates or an orthopedic operation has been needed to bone metastasis of lung cancer. We presented the lung cancer case who showed the symptoms in transcervical pathologic fracture and whose QOL was improved by orthopedic surgery, radiotherapy to bone metastasis, chemotherapy, gamma knife surgery, and treatment with zoledronic acid and gefitinib.

Prospective study of HDR (192Ir) versus MDR (137Cs) intracavitary brachytherapy for carcinoma of the uterine cervix.

PURPOSE: The aim of this study was to compare the results of high-dose rate (HDR) and medium-dose rate (MDR) intracavitary brachytherapy for carcinoma of the uterine cervix on the basis of a prospective study and to determine the dose rate conversion factor (DRCF) from low-dose rate (LDR) to MDR via HDR, because a DRCF of 0.54 from LDR to HDR has been widely accepted. MATERIALS AND METHODS: Between August 1991 and July 1999, 104 patients were entered into this trial to compare results between HDR (n=54) and MDR (n=50). Three patients were excluded from this study, leaving 54 HDR patients and 47 MDR patients eligible. Method and dose of external beam radiotherapy were the same for both groups. For HDR intracavitary brachytherapy, point A dose was adjusted to 32 Gy/4 fractions for stages I and II, to 30 Gy/4 fractions for stage III, and to 22.5 Gy/3 fractions for stage IV. The corresponding values for MDR were 35.6 Gy/4 fractions, 34 Gy/4 fractions, and 25.5 Gy/3 fractions. The average dose rate at point A was 30 Gy/hour (9.0-65.2) for HDR and 1.7 Gy/hour (1.3-2.2) for MDR. We assumed a DRCF of 0.9 from MDR to HDR. RESULTS: The 3-year cause-specific survival rates for HDR were 85%, 83%, 75%, and 0% for stages I, II, III, and IV, respectively. The corresponding figures for MDR were 100%, 82%, 58%, and 40%. Six of the HDR patients (11%) and 2 of the MDR patients (4%) developed Kottmeier's grade 2 or 3 late complications. A DRCF of 0.6 from LDR to MDR could be derived from a DRCF of 0.9 from MDR to HDR and one of 0.54 from LDR to HDR. CONCLUSIONS: There were no statistically significant differences in cause-specific survival and incidence of late complications between HDR and MDR. A DRCF of 0.6 from LDR to MDR could be determined. However, because the results of this trial were preliminary, a further study is needed.

CyberKnife stereotactic irradiation for metastatic brain tumors.

BACKGROUND: The CyberKnife provides a new technique for performing frameless stereotactic irradiation. So far, few reports have been published on clinical outcomes obtained with the CyberKnife. This report summarizes our clinical experience with CyberKnife irradiation for metastatic brain tumors. MATERIALS AND METHODS: Seventy-seven lesions (48 patients) were evaluated and analyzed, and 66 lesions in 41 patients were treated with stereotactic radiosurgery (SRS). The prescribed dose was 9 to 30 Gy. RESULTS: Freedom from progression of the tumors was more likely with a prescribed dose of at least 24 Gy than with one of less than 20 Gy (p=0.0244; log-rank test). The CR (complete response) rate was significantly higher when D99 was at least 24 Gy (p=0.0045). There were no severe side effects. CONCLUSION: Stereotactic irradiation with the CyberKnife for metastatic brain tumors is effective and safe. D99 should be at least 24 Gy for CyberKnife SRS treatment.

[CyberKnife]

The CyberKnife is an image-guided robotic system designed for stereotactic radiosurgery. This system uses a lightweight, x-band linear accelerator, computer-controlled robotic arm, a pair of orthogonal x-ray imagers (TLS: Target Locating System), and a computer workstation. During the treatment, the TLS determines the location of the lesion and communicates these coordinates to the robot. The robot adjusts the position of the beam to the target. The accuracy of this system is 0.7 mm (median) at Osaka University. The CyberKnife system offers new options for radiosurgery/therapy. Stereotactic fractionated radiotherapy can now be performed with the same accuracy as single-fraction stereotactic radiosurgery. The frameless nature of CyberKnife allows tumors in the chest and abdomen to be treated as well. The real time tracking system option enables one to treat tumors that move with respiration, such as lesions in lung. Tumors in the lower spine, pancreas, and lung have already been treated in the USA. A description of the components, accuracy, and future of the CyberKnife will be presented.